Field of the Invention
The present invention relates to a pharmaceutical composition and a method for preventing or treating various amyloid β-caused diseases.
“The Sequence Listing submitted in text format (.txt) on Jan. 10, 2013, named “PP100055US RSequenceListing.txt”, (created on Jan. 3, 2013, 4KB), is incorporated herein by reference.”
Description of the Related Art
Alzheimer's disease (AD) is a progressive neurodegenerative disorders which affects approximately twenty four million people worldwide, and it is the most common form of dementia among older people. AD is characterized by progressive memory impairment and cognitive dysfunction. A distinct hallmark of AD is the deposition of amyloid plaques which are mainly composed of amyloid β (Aβ) of 40, 42, and 43 amino acids in length. Aβ is produced by the sequential cleavage of the amyloid β precursor protein (APP) by β- and γ-secretases1,2. Aβ can exist in different forms such as monomers, oligomers (dimer, trimer, and tetramer), proto-fibrils, and fibrils, and these different conformational states are related to its toxicity. Oligomeric Aβ was shown to be approximately 10- and 40-fold more cytotoxic than fibrillar and monomeric Aβ, respectively3. A recent report also found that dimeric Aβ are 3-fold more toxic than monomeric Aβ, and that trimeric and tetrameric Aβ are upto 13-fold more toxic4.
Although Aβ unquestionably plays a causative role in AD, the underlying mechanisms by which it contributes to the development of this disease are still controversial. It is widely accepted that Aβ exerts its pathological activity extracellularly. In pathological AD brains, Aβ is secreted into the extracellular space forming amyloid plaques5. When added into the culture media, Aβ can induce cell death in vitro in a variety of cell types3,4,6.
However, accumulating evidence suggests that intracellular Aβ activity is also critical for the development of AD. Several authors have reported the intracellular localization of Aβ in the brain tissues of post-mortem AD patients and in transgenic AD mice1,7,8. A closer examination with electron microscopy and immunocytochemistry revealed that Aβ is present in diverse subcellular organelles in neuronally differentiated P19 cells, including early endosomes, trans-Golgi network, rough endoplasmic reticulum, outer mitochondrial membrane, and nuclear envelope9. In a triple transgenic AD mouse model, early cognitive impairments correlated with the accumulation of intracellular Aβ in the hippocampus and amygdala, without the apparent deposition of amyloid plaques or neurifibrillary tangles10.
Intracellular Aβ was also shown to induce p53-dependent neuronal cell death11,12 through the impairment of mitochondrial function13. The intra-hippocampal injection of an antibody directed against Aβ reduced not only extracellular Aβ deposits, but also intracellular Aβ accumulation. Upon dissipation of this antibody, the re-appearance of the extracellular deposits was preceded by the accumulation of intracellular Aβ. These observations suggest that a dynamic exchange between intracellular and extracellular Aβ exists, and that intracellular Aβ serves as a source of extracellular amyloid deposits, implying a role for intracellular Aβ in the pathogenesis of AD14,15.
Since the accumulation of Aβ is considered to be the most critical single event in the pathogenesis of AD, a catabolic elimination of Aβ from the brain would be a valuable therapeutic strategy. Several proteases, including neprilysin (NEP), insulin degrading enzyme, endothelin-converting enzyme, and uPA/tPA-plasmine, have been identified for their ability to degrade Aβ16, with NEP being the best-characterized one. The pharmacological inhibition or genetic ablation of NEP in mice has been shown to result in an increased Aβ deposition, accompanied by deficits in synaptic plasticity and an impairment in hippocampus-dependent memory17,18, while the viral or transgene-mediated overexpression of NEP reduced Aβ deposition and its associated cytopathology19,20. However, it was recently shown that NEP overexpression did not reduce the oligomeric Aβ levels or improve deficits in learning and memory. These results appear to suggest that the NEP-dependent degradation of Aβ affected plaques more efficiently than oligomeric Aβ21.
Throughout this application, various patents and publications are referenced, and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.